Experience has long shown that pharmaceuticals or other items for human or animal consumption may be safely and conveniently packaged in a hard or soft gelatin (softgel) shell. Gelatin is a substantially pure protein food ingredient, obtained by the thermal denaturation of collagen, which is the most common structural material and most common protein in animals. Gelatin forms thermally reversible gels with water, and the gel melting temperature (<35° C.) is below that of human body temperature (37° C.), which gives gelatin products unique properties, such as reversible sol-gel transition states at near physiologic temperatures.
Gelatin is an amphoteric protein with an isoionic point between 5 and 9, depending on raw material and method of manufacture. Type A gelatin, with an isoionic point of 7 to 9, is derived from collagen with acid pretreatment. Type B gelatin, with an isoionic point of 4.8 to 5.2, is the result of alkaline pretreatment of the collagen. Like its parent protein collagen, gelatin is unique in that in contains, approximately, 16% proline, 26% glycine, and 18% nitrogen. Gelatin is not a complete protein food because the essential amino acid tryptophan is missing and the amino acid methionine is present only at a low level.
There are a large number of processes used in the manufacture of gelatin and the raw materials from which it is derived, which includes demineralized bone, pigskin, cowhide and fish. Gelatin can be derived from any edible material containing collagen. For reasons of economy, gelatin can be most practically be derived from collagen sources which would normally require refining before consumption or which would otherwise make up protein-containing waste material destined for animal feeds, agricultural fertilizers, or for other industries.
Gelatin capsules are traditionally divided into two general groups; hard shell gelatin capsules and soft gelatin capsules (softgels). In hard shell gelatin capsules, the capsule is in equilibrium with a relative humidity of less than 20%; they are formulated with a low ratio of dry plasticizer to dry gelatin (low amounts of plasticizer); and are traditionally made of two separately formed, cooperating, telescoping shells. On the other hand, softgels are most commonly in equilibrium with a relative humidity of between 20% and 30%, are formulated with a high ratio of dry plasticizer to dry gelatin (higher amounts of plasticizer); and are traditionally formed in a unitary process such as the rotary die encapsulation process described below.
Filled one-piece soft capsules or softgels have been widely known and used for many years and for a variety of purposes and are capable of retaining a liquid fill material. The fill material may vary from industrial adhesives to bath oils. More commonly, the softgels are used to enclose or contain consumable materials such as vitamins and pharmaceuticals in a liquid vehicle or carrier.
Encapsulation within a soft capsule of a solution or dispersion of a nutritional or pharmaceutical agent in a liquid carrier offers many advantages over other dosage forms, such as compressed, coated or uncoated solid tablets, or bulk liquid preparations. Encapsulation of a solution or dispersion permits accurate delivery of a unit dose, an advantage which becomes especially important when relatively small amounts of the active ingredient must be delivered, as in the case of certain hormones. Such uniformity is more difficult to achieve via a tableting process wherein solids must be uniformly mixed and compressed, or via incorporation of the total dose of active ingredient into a bulk liquid carrier which must be measured out prior to each oral administration.
Encapsulation of drugs in soft capsules further provides the potential to improve the bioavailability of pharmaceutical agents. Active ingredients are rapidly released in liquid form as soon as the shell ruptures. Complete disintegration of the capsule is not necessary for the active ingredients to become available for absorption, unlike the case of tableted compositions. Also, relatively insoluble active ingredients can be dispersed in a liquid carrier to provide faster absorption. A typical example involves a solution of a hydrophobic drug in a hydrophilic solvent. Upon ingestion, the shell ruptures in the stomach and the hydrophilic solution dissolves in the gastric juice. Acid soluble compounds remain in solution and are readily available for rapid absorption. Acid insoluble compounds may precipitate temporarily, in the form of a fine particle dispersion, but then redissolve quickly to give a solution with good bioavailability.
Soft capsules, most commonly, soft gelatin capsules, provide a dosage form which is readily accepted by patients, since the capsules are easy to swallow and need not be flavored in order to mask the unpleasant taste of the active agent. Soft capsules are also more easily transported by patients than bulk liquids, since only the required number of doses need be removed from the package.
Traditionally, both soft and hard-shell capsules have been manufactured using mammalian gelatin as the material of choice for producing the capsule envelope. The rotary die process developed by Robert Scherer in 1933 for producing one piece soft capsules utilizes the unique properties of gelatin to enable a continuous soft capsule manufacturing process. The inventive encapsulation system disclosed in this patent application is especially useful in the rotary die method of soft capsule manufacture.
Conventional manufacturing of soft capsules using the rotary die process utilizes mammalian gelatin in a process well known to those of skill in the art. Dry gelatin granules are combined with water and suitable plasticizers and the combination is then mixed and heated under vacuum to form a molten gelatin mass. The gelatin mass is held in its molten state while being formed or cast into films or ribbons on casting wheels or drums. The films or ribbons are fed under a wedge and between rotary encapsulation dies. Within the encapsulation dies, capsules are simultaneously formed, in pockets in the dies, from the films or ribbons, then filled, cut, and sealed. The seals are formed via a combination of pressure and heat as the capsule is filled and cut. Rotary die manufacture of soft gelatin capsules is disclosed in detail in The Theory and Practice of Industrial Pharmacy (Lachman, Lieberman and Kanig, Editors), 3rd Edition, published by Lea & Febiger. A good description of gelatin encapsulation techniques can also be found in WO 98/42294 (PCT/GB98/00830).
Gelatin formulations used to produce films suitable for making capsules within the rotary die process typically contain between 25% to 45% by weight mammalian gelatin. Levels below 25% by weight tend to lead to poor sealing of the capsule. The physical properties of the gelatin film are critical to the economic production of soft capsules. For example, the film must be strong enough to survive manipulation in the encapsulation machine, provide good sealing properties at temperatures below the melting point of the film, evidence rapid dissolution in gastric juices, and have sufficient elasticity to allow for the formation of the capsule.
There are, however, significant problems associated with gelatin capsules. In the case of gelatins derived from mammalian gelatin, there are concerns regarding the possible transmission of prions that are believed responsible for syndromes such as bovine spongiform encephalopathy (BSE or “mad cow” disease) and Jacob-Creutzfeldt Syndrome. There are also ethical, cultural, dietary, and religious restrictions in various parts of the world against products derived from certain animals. To answer concerns about the safety and consumer acceptability of mammalian gelatins, gelatins have been derived from fish sources, however, fish gelatins have particular fabrication requirements and are likely to become increasingly expensive with the depletion of the world's fish resources.
Regardless of the ultimate source of the gelatin from either mammal or fish sources, none of these approaches have answered what may be the most fundamental problem regarding gelatin encapsulation, namely, that not all substances and compounds may be successfully encapsulated, in a gelatin capsule.
Not all liquids are suitable as vehicles or carriers for the fill of a softgel. For example, water, propylene glycol, glycerin and low molecular alcohols, ketones, acids, amines and esters cannot be filled in softgels by themselves, or may only be present in small amounts. In particular, concentrations of water in the fill of greater than 20% by weight will dissolve the gelatin shell. Liquids that are suitable for filling softgels vary from water immiscible liquids such as vegetable oils, aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers and esters, to water miscible nonvolatile liquids. Examples of other acceptable carriers include polyethylene glycols and nonionic surfactants and other pharmaceutically acceptable solvent systems.
Even if the fill liquid is amenable to gelatin encapsulation, there are specified limitations to the use of certain fill vehicles for softgels. For example, the pH of the fill liquid should not be below 2.5 or above 7.5. At pH's below 2.5, the gelatin is hydrolyzed causing leaking, whereas at pH's greater than 7.5, the gelatin can also be hydrolyzed. Moreover, emulsions of oil/water or water/oil are not suitable for softgel encapsulation because the emulsions eventually break down, releasing water which dissolves the gelatin shell. The solvent or carrier in some cases must have sufficient solvating power to dissolve a large amount of the pharmaceutical agent to produce a highly concentrated solution, and yet not hydrolyze, dissolve, or discolor the gelatin shell.
Even when provided a suitable carrier and suitable agent for encapsulation, there can be problems in successful commercial encapsulation. One problem occurs with agents of low solubility that require a relatively large volume of solvent for solubilization, leading to the necessity for a large capsule. Often, it is not possible to dissolve the pharmaceutical agent in a volume of solvent small enough to produce a softgel that is appropriate from the standpoint of economics and patient acceptance.
Recently, various systems for increasing the solubility of low-solubility active ingredients have been described as, for example, in U.S. Pat. Nos. 5,071,643 and 5,360,615 to Yu, et al. These systems involve the titration of, as appropriate, acid or alkali into polyethylene glycol (PEG) containing a low-solubility pharmaceutical agent. In particular, the creation of a salt of a weak acid and strong alkali, such as potassium hydroxide or sodium hydroxide, markedly increases the solubility of the pharmaceutical agent in PEG. However, by converting a portion of the pharmaceutical agent to the salt of a weak acid and strong alkali and thereby increasing the solubility, hydroxide ion (—OH) is necessarily present as a reacting species and is available for degradation of the gelatin. This may occur by hydrolysis of the gelatin, a disruption of the ionic bonding between the gelatin helices, or by a combination of the two, along with other possible mechanisms. In fact, it is a long-established and widely held tenet of pharmaceutical chemistry that such salts cannot be encapsulated in gelatin capsules, unless they are highly diluted.
Thus, under the prior art, the pharmaceutical chemist is often faced with a true dilemma, desiring to use alkali to increase the solubility of a recalcitrant pharmaceutical agent in order to formulate a capsule small enough for commercial acceptance and/or to stabilize the drug substance; while at the same time being forced to restrict the use of alkali lest the capsule be impermissibly degraded.
Particular note must be taken of the need to formulate capsules that satisfy commercial, rather than theoretic, utility. While it may be possible to formulate certain basic fills in gelatin capsules as an initial matter of encapsulation, such formulations, as will be described below, are unable to satisfy the stability standards for commercial pharmaceutical products. Therefore, as will be seen below, it has, in the prior art, remained extremely difficult as a practical matter to encapsulate many basic substances in soft gelatin capsules.
A prototypical example of a pharmaceutical agent that has proven difficult to encapsulate in soft gelatin capsules is acetaminophen (APAP). Utilizing the enhanced solubility system described in U.S. Pat. Nos. 5,071,643 and 5,360,615 to Yu, et al.; Shelley et al. found, as taught in U.S. Pat. No. 5,505,961, that the sodium hydroxide or potassium hydroxide required to solubilize the acetaminophen at very high concentrations (those greater than about 27% by weight), increased the pH of the PEG solution to greater than 12, resulting in the degradation of the acetaminophen and the dissolving of the softgel shell.
By adding, inter alia, propylene glycol and polyvinylpyrrolidone, Shelley et al. were able to achieve concentrations of acetaminophen in a stable gelatin capsule preparation to 40% by weight, but not significantly more. Such an advance had the effect of obtaining the same size softgel for a 325 mg dose as for a 250 mg dose softgel product under the prior art. While significant, this still falls short of the desired dosage capabilities, which range even higher in the case of prescription formulated acetaminophen.
Such a problem in achieving suitable dosage systems wherein the active or actives must be formulated as a high concentration preparation is not restricted to acetaminophen, but also includes, by way of illustration and not limitation, such well-known drugs as ibuprofen, naproxen, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, doxylamine succinate, guafenesin, diphenhydramine, aspirin, and caffeine; as well as certain dosage forms and concentrations of ranitidine, cimetidine, celecoxib, ritonavir, and fexofenadine; in addition to many others and combinations of the above enumerated drugs.
What has been needed, and heretofore unavailable, is a system for encapsulating those pharmaceutical agents and carriers that have heretofore proved refractory to encapsulation in gelatin capsules, due either to the effect of the concentration of the agent or carrier, or the basic nature of the fill. The present invention has solved this problem by a novel and unexpected use of a drug delivery system of a non-gelatin capsule shell resistant to alkali and, in one embodiment, a partially neutralized drug in which the provision of the salt of a weak acid and a strong alkali produced significantly high drug concentrations in acceptable quantities of solvent.